SUMMARY Pancreatic ? cell regeneration is a promising approach for the treatment of insulin dependent type-1 (T1D) and -2 diabetes (T2D). However, the nature of the signaling pathway(s) responsible for the age-dependent decline of ? cell proliferation remains an enigma, a significant roadblock in diabetes therapy. The Kulkarni laboratory at Joslin Diabetes Center recently reported that SerpinB1 secreted from the liver promotes ? cell proliferation (El Ouaamari et al. Cell Metabolism 2016) while the Qi laboratory at the University of Michigan showed that Toll- Like Receptors 2 and 4 (TLR2/TLR4) signaling pathways, two redundant innate immune signaling pathways, block diet-induced ? cell replication (Nat Immunol, under revision). In this application, the Kulkarni and Qi laboratories will team up to test an overarching hypothesis that the antagonistic interplay between SerpinB1 and TLR2/TLR4 maintains a balance in favor of ? cell regeneration in both mice and humans under diabetogenic stimuli. We propose that TLR2/TLR4 activation in diet-induced obesity blocks SerpinB1-mediated ? cell replication while simultaneous disruption of TLR2/TLR4 signaling pathways on ? cells may promote ? cell proliferation via SerpinB1-dependent manner. To this end, we will (i) perform lineage tracing to test the hypothesis that TLR2/TLR4 regulates ? cell replication in a ? cell autonomous manner; (ii) delineate the interplay between TLR2/TLR4 and SerpinB1 and the underlying mechanism in the regulation of ? cell regeneration; and (iii) determine the therapeutic potential of targeting TLR2/TLR4 and SerpinB1 in ? cell proliferation and regeneration using human ? cells and islets. Hence, this study will be instrumental in demonstrating that metabolic and innate immune systems, two primitive systems critical for the long-term homeostasis of multi-cellular organisms, have evolved to promote cooperative, adaptive responses against diverse environmental challenges such as overnutrition. If successful, this study will help realize therapeutic potential of our discoveries and benefit millions of diabetic patients worldwide by delivering novel, invaluable therapeutics for the treatment of widespread diabetes. RELEVANCE TO HUMAN HEALTH: This application, with parallel mouse models and human islets studies, will reveal novel molecular and cellular mechanisms, shaped by metabolic and innate immunity signaling pathways, which govern ? cell replication and metabolic homeostasis. Hence, this study may fundamentally change our views of metabolic-innate immune interactions, and hold tremendous promise to uncover both novel disease mechanisms and pharmacological targets aimed at treating and reversing the underlying metabolic imbalances in diabetes.